Interpreting biochemical control response rates with first-generation somatostatin analogues in acromegaly

Annamaria Colao1 • Renata S. Auriemma1 • Rosario Pivonello1 • Leandro Kasuki2 •

Monica R. Gadelha2

Published online: 30 October 2015

� The Author(s) 2015

Abstract

Context The somatostatin analogues octreotide LAR and

lanreotide Autogel have been evaluated for the treatment of

acromegaly in numerous clinical trials, with considerable

heterogeneity in reported biochemical response rates. This

review examines and attempts to account for these differ-

ences in response rates reported in the literature.

Evidence acquisition PubMed was searched for English-

language studies of a minimum duration of 24 weeks that

evaluated C10 patients with acromegaly treated with

octreotide LAR or lanreotide Autogel from 1990 to March

2015 and reported GH and/or IGF-1 data as the primary

objective of the study.

Evidence synthesis Of the 190 clinical trials found, 18

octreotide LAR and 15 lanreotide Autogel studies fulfilled

the criteria for analysis. It is evident from the protocols of

these studies that multiple factors are capable of impacting

on reported response rates. Prospective studies reporting an

intention-to-treat analysis that evaluated medically naıve

patients and used the composite endpoint of both GH and

IGF-1 control were associated with lower response rates.

The use of non-composite biochemical control endpoints,

heterogeneous patient populations, analyses that exclude

treatment non-responders, assay variability and prior

responsiveness to medical therapy are just a few of the

factors identified that likely contribute to higher success

rates.

Conclusions The wide range of reported response rates

with somatostatin analogues may be confusing and could

lead to misinterpretation by both the patient and the

physician in certain situations. Understanding the factors

that potentially drive the variation in response rates should

allow clinicians to better gauge treatment expectations in

specific patients.

Keywords Acromegaly � Octreotide � Lanreotide �Pasireotide � Somatostatin analogue � Response rate

Introduction

Acromegaly is almost always caused by a growth hormone

(GH)-secreting pituitary tumor and is associated with

increased morbidity and mortality [1]. Prompt treatment is

essential in order to abrogate potentially life-threatening

complications. Clinical practice guidelines advocate a

multi-component therapeutic approach which includes

lowering of both serum GH and insulin-like growth factor

1 (IGF-1) levels, tumor volume reduction, and amelioration

of signs, symptoms and co-morbidities [1–3]. Somatostatin

analogues, such as long-acting formulations of octreotide

(octreotide LAR) and lanreotide (lanreotide Autogel), are

recommended as first-line medical treatment for patients

with acromegaly [2]. Octreotide LAR and lanreotide

Autogel have been evaluated for the treatment of acro-

megaly in numerous clinical trials, with heterogeneity in

reported biochemical response rates [4]. Studies of

octreotide LAR prior to 2006 suggested that 50–70 % of

patients with acromegaly respond to octreotide LAR [5–9].

In line with this, in a meta-analysis by Freda et al. [10]

& Annamaria Colao

colao@unina.it

1 Dipartimento di Medicina Clinica e Chirurgia, Universita

Federico II di Napoli, Via S Pansini 5, 80131 Naples, Italy

2 Endocrine Unit, Hospital Universitario Clementino Fraga

Filho, Universidade Federal do Rio de Janeiro,

Rio de Janeiro, Brazil

123

Pituitary (2016) 19:235–247

DOI 10.1007/s11102-015-0684-z

examining trials published before 2004, overall response

rates for octreotide LAR were determined to be 57 % in

terms of GH control and 67 % in terms of normalization of

IGF-1. Additional studies of octreotide LAR [11, 12] and

lanreotide Autogel [13, 14] published shortly after reported

biochemical response rates as high as 70–80 %. More

recently, however, response rates in prospective clinical

trials of octreotide LAR, lanreotide Autogel and the mul-

tireceptor-targeted somatostatin analogue pasireotide have

been substantially lower (17–41 %) [15–23].

The purpose of this review is to examine and attempt to

account for the differences in response rates reported in the

literature for first-generation somatostatin analogues.

Where appropriate, examples will be provided to illustrate

how various factors may affect reported outcomes. Clinical

study results will also be discussed in order to help prac-

titioners treating patients with acromegaly put results from

published clinical trials into context.

Selection of studies for review

PubMed was searched for English-language studies eval-

uating patients with acromegaly treated with octreotide

LAR or lanreotide Autogel from 1990 (i.e., prior to the

development of either drug formulation) to March 2015.

Search terms used were ‘‘acromegaly and octreotide’’ and

‘‘acromegaly and lanreotide’’; results were filtered for

‘‘clinical trial’’. Studies that were included had C10

patients, a minimum duration of 24 weeks, used octreotide

LAR or lanreotide Autogel as either first-line therapy or

after previous surgery, radiotherapy or medical therapy,

and reported GH and/or IGF-1 data as the primary objec-

tive of the study.

Of the 190 ‘‘clinical trials’’ found using ‘‘acromegaly

and octreotide’’, 18 studies fulfilled our criteria for analysis

(Table 1) [5–9, 11, 12, 14–19, 24–28]. Of the 83 ‘‘clinical

trials’’ found using ‘‘acromegaly and lanreotide’’, 15

studies fulfilled our criteria for analysis (Table 2) [13, 14,

20–23, 29–36].

Factors that may impact on response rates

A recent meta-analysis by Carmichael et al. [37] that

looked into how various aspects of acromegaly clinical trial

methodology impact on reported response rates to

somatostatin analogues concluded that year of publication,

study duration and prior somatostatin analogue use sig-

nificantly affected response rates. This analysis looked at

how single factors might affect outcomes, rather than a

combination of factors. There are many aspects to clinical

studies that can potentially affect reported response rates,

including the definition of response, the characteristics of

the enrolled patients, whether or not all of the patients

recruited into the study were included in the analysis, and

whether the study was prospective or retrospective, among

others. Most studies will be associated with a number of

these factors, all of which can affect reported response

rates.

Patient population

Clinical trials of any drug in any disease area select

patients for enrollment into the study through a series of

inclusion and exclusion criteria. These criteria are neces-

sary to ensure that the correct patient population is treated

for the hypothesis being examined, and in acromegaly may

include such factors as sex, age, previous treatment history

(e.g., transsphenoidal surgery, radiotherapy or medical

therapy), and the presence or absence of other medical

conditions.

Evaluating a drug effect in different subpopulations of

patients with acromegaly may result in differing outcomes.

In early studies of octreotide LAR and lanreotide Autogel,

most studies included patients who were known responders

to the drug (Tables 1, 2). As octreotide LAR and lanreotide

Autogel were new formulations of the available drugs, this

inclusion criterion was chosen to show that the new for-

mulations were as effective as the older formulations in

order to gain market approval. However, if taken out of

context, the reported response rates may appear relatively

high when compared with more recent results in which

patients were not selected for prior responsiveness. For

example, early studies of octreotide LAR (Lancranjan et al.

[8], [9]) and lanreotide Autogel (Caron et al. [29]), which

included patients known to be responsive to subcutaneous

(sc) octreotide immediate release and lanreotide slow

release (SR), respectively, showed GH response rates of

55–69 % [8, 9, 29] and IGF-1 response rates of 48–65 %

[8, 9, 29]. Most of the patients in these studies had also

received prior transsphenoidal surgery and/or radiotherapy.

More recently, somatostatin analogues have been eval-

uated as first-line therapy, in which the enrolled patients

had not previously received any treatment for acromegaly.

The percentage of patients achieving the composite end-

point of both GH and IGF-1 control after 1 year of treat-

ment in prospective studies of patients with previously

untreated acromegaly was 17–27 % with octreotide LAR

[16–18] and 33–54 % with lanreotide Autogel [22, 33].

Additionally, the recent randomized, double-blind study of

pasireotide LAR versus octreotide LAR by Colao et al. [19]

in patients who were either de novo or had received

transsphenoidal surgery (but no medical therapy and no

radiotherapy within 10 years) reported that 19 % of

octreotide LAR recipients and 31 % of pasireotide LAR

236 Pituitary (2016) 19:235–247

123

Table

1SummaryofoctreotideLARstudiesin

acromegaly:studyparam

etersandbiochem

ical

endpoints

Publication

nTrial

design

Trial

duration

Patientpopulation

Dose

titration

GH

andIG

F-1

entrycriteria

Target

threshold

values

forGH

andIG

F-1

Biochem

ical

controlrates

Previoustreatm

ent

Priorresponse

toSSA

GH

n(%

)

IGF-1

n(%

)

GH

?IG

F-1

n(%

)

Lancranjan

etal.[8]

101

OL,P

30mo

TSS?

oct

sc(n

=101)

83pts

wereconsidered

goodrespondersto

oct

sc

Dose-rangingstudy:suppressionofGH

andIG

F-1

assessed

Biochem

ical

controlnotdefined

55(55)a

66(65)b

–

Daviesetal.[7]

13

OL,P

1–3yr

TSS(n

=2);RT(n

=1);

TSS?

RT(n

=4);Y

implant

(n=

1);denovo(n

=5)

Pts

notselected

forprior

response

Dose-rangingstudy:suppressionofGH

andIG

F-1

assessed

Biochem

ical

controlnotdefined

6(46)c

7(54)d

–

Lancranjan

etal.[9]

151

OL,P

12mo

Oct

sc(n

=49);TSS?

oct

sc

(n=

56);RT?

octsc

(n=

8);

TSS?

RT?

oct

sc(n

=38)

Only

pts

with

GH\

10lg/L

during

C4wktreatm

entwith

oct

scwereselected

Individualized

accordingto

the

meanGH

afterthe

seconddose

GH[

2lg/L

afterOGTT

andelevated

IGF-1

GH

B2.5

lg/L

IGF-1

norm

al

104(69)

98(65)

–

Colaoet

al.[5]

36

OL,P

24mo

TSS(n

=5);TSS?

oct

sc

(n=

5);TSS?

oct

LAR

(n=

3);TSS?

lanSR

(n=

8);denovo(n

=15)

16/21pts

withprevious

surgeryreceived

oct

sc

Uptitrated

in15pts

withGH[

5lg/L

GH[

2lg/L

afterOGTT

andelevated

IGF-1

forage

GH

B2.5

lg/L

IGF-1

norm

al

20(56)

19(53)

–

Cozziet

al.[6]

110

OL,

Ret

18–54

mo

TSS?

oct

LAR

(n=

29);

RT?

oct

LAR

(n=

7);

TSS?

RT?

oct

LAR

(n=

23);oct

sc(n

=39);de

novo(n

=12)

Pts

had

tohaveaGH

and/orIG

F-1

decrease

ofat

least20%

aftera

6-m

onth

trialwithoct

LAR

Individualized

to

achievenorm

al

age-adjusted

IGF-1

levelsandGH

\2.5

lg/L

GH[

1lg/L

afterOGTT

andelevated

IGF-1

forage

GH\

2.5

lg/L

IGF-1

norm

al

79(72)e

83(75)e

–

Ayuketal.[24]

91f

OL,

Ret

48wk

Oct

sc(n

=34);TSS?

oct

sc

(n=

29);RT?

octsc

(n=

5);

TSS?

RT?

oct

sc(n

=23)

Only

patients

who

completed48wk

treatm

entwere

considered

Individualized

accordingto

the

meanGH

afterthe

seconddose

GH[

2lg/L

afterOGTT

andelevated

IGF-1

GH\

2.0

lg/L

61(67)

48(72)

–

Jallad

etal.

[25]

80

OL,P

12mo

TSS?

oct

LAR

(n=

24);

TSS?

RT?

oct

LAR

(n=

28);lan(n

=14);DA

(n=

1);denovo(n

=13)

Pts

notselected

forprior

response

Individualized

to

achievenorm

al

age-adjusted

IGF-1

levels

GH[

1lg/L

afterOGTT

andelevated

IGF-1

forage

andsex

GH\

2.5

lg/L

IGF-1

norm

al

34(43)

20(25)

–

Cozziet

al.

[12]

67

OL,P

6–108

mo

Denovo(n

=67)

Pts

notselected

forprior

response

Individualized

at3-

to6-m

ointervalsif

GH

orIG

F-1

levels

remained

elevated

GH[

1lg/L

afterOGTT

andelevated

IGF-1

forage

GH\

2.5

lg/L

IGF-1

norm

al

46(69)e

47(70)e

38(57)e

Colaoet

al.

[11]

56

OL,

Ret

24mo

Denovo(n

=56)

16pts

wereexcluded

from

theefficacy

analysisbecause

of

lack

ofresponse

before

24mo

Uptitrationin

pts

withIG

F-1

levels

abovethenorm

al

rangeand/or

GH[

2.5

mg/L

GH[

1lg/L

afterOGTT

andelevated

IGF-1

forage

GH

B2.5

lg/L

IGF-1

norm

al

48(86)

47(84)

45(80)

Pituitary (2016) 19:235–247 237

123

Table

1continued

Publication

nTrial

design

Trial

duration

Patientpopulation

Dose

titration

GH

andIG

F-1

entrycriteria

Target

threshold

values

forGH

andIG

F-1

Biochem

ical

controlrates

Previoustreatm

ent

Priorresponse

toSSA

GH

n(%

)

IGF-1

n(%

)

GH

?IG

F-1

n(%

)

Mercadoet

al.

[18]

98

OL,P

48wk

Denovo(n

=98)

Pts

notselected

forprior

response

Uptitrationin

pts

withGH[

2.5

lg/

LorIG

F-1

above

theadjusted

norm

al

rangeat4and6mo

GH[

1lg/L

afterOGTT

andIG

F-

1[

97th

percentile

of

thenorm

al

rangeforage

andsex

GH

B2.5

lg/L

IGF-1

norm

al

30(31)

23(23)

17(17)

Andries

etal.

[28]

12

OL,R,

P,CO

12mo

TSSalone(n

=4);

TSS?

radiotherapy(n

=3);

oct

LAR

(n=

11)

4ptshad

controlofboth

GH

andIG

F-1

atstudy

entry

––

GH\

0.38lg/L

IGF-1

norm

al

5(42)

5(42)

4(33)

Colaoet

al.

[16]

48

OL,R,

P

48wk

Denovo(n

=48)

Pts

notselected

forprior

response

Uptitrationin

pts

withmeanGH

[2.5

lg/L

and/or

elevated

IGF-1

at3

and6mo

GH[

1lg/L

afterOGTT

andIG

F-

1[

97th

percentile

for

ageandsex

GH

B2.5

lg/L

IGF-1

norm

al

––

13(27)

Ghigoet

al.

[26]

56

OL,R,

P

12mo

Allptsnaıveto

medical

therapy

andRT;TSSin

anunreported

number

ofpts

Pts

notselected

forprior

response

Uptitrationin

pts

withIG

F-1

within

20%

below

ULN

or[

ULN

every

16wk

GH[

1lg/L

afterOGTT

andIG

F-

1C

1.3xULN

IGF-1

norm

al–

19(34)

–

Okiet

al.[27]

30

OL,Ret

24mo

TSSalone(n

=12);TSS?

DA

(n=

11);TSS?

radiotherapy

(n=

1);

TSS?

radiotherapy?

DA

(n=

5);denovo(n

=1)

Pts

notselected

forprior

response

Uptitrationin

pts

withmeanGH

[2.5

lg/L

and/or

elevated

IGF-1

every3mo

–GH

B2.5

lg/L

IGF-1

norm

al

17(57)

16(53)

11(37)

Karacaet

al.

[17]

11

R,P

12mo

Denovo(n

=11)

Pts

notselected

forprior

response

Dose

titration

accordingto

biochem

ical

response

at3,6and

12mo

–GH

B2.5

lg/L

IGF-1

norm

al

9(82)

3(27)

3(27)

Carlsen

etal.

[15]

32

R,P

24wk

Denovo(n

=11)

Pts

notselected

forprior

response

Fixed

dose

GH[

5mIU

/L

afterOGTT

GH

B2mIU

/L

duringOGTT

IGF-1

BULN

11(34)

10(31)

7(22)

Tutuncu

etal.

[14]

36

OL,Ret

18mo

TSS(n

=36)

Pts

notselected

forprior

response

Dose

titration

accordingto

biochem

ical

response

at6mo

GH[

1lg/L

afterOGTTor

mean

GH[

5lg/L

andIG

F-

1[

ULN

for

ageandsex

GH

B2.5

lg/L

IGF-1

norm

al

24(67)

24(67)

23(64)

238 Pituitary (2016) 19:235–247

123

Table

1continued

Publication

nTrial

design

Trial

duration

Patientpopulation

Dose

titration

GH

andIG

F-1

entrycriteria

Target

threshold

values

forGH

andIG

F-1

Biochem

ical

controlrates

Previoustreatm

ent

Priorresponse

toSSA

GH

n(%

)

IGF-1

n(%

)

GH

?IG

F-1

n(%

)

Colaoet

al.

[19]

182

R,P,

DB

12mo

TSS(n

=80);RT(n

=1);

denovo(n

=101)

Pts

notselected

forprior

response

Optional

uptitration

inpts

withmean

GHC2.5

lg/L

and/

orIG

F-1[

ULN

at

3and7mo

GH[

1lg/L

afterOGTTor

mean

GH[

5lg/L

andIG

F-

1[

ULN

for

ageandsex

GH\

2.5

lg/L

IGF-1

norm

al

94(52)

43(24)

35(19)

CO

crossover,DAdopam

ineagonist,DBdouble

blind,GH

growth

horm

one,IG

F-1

insulin-likegrowth

factor1,lanlanreotide,LARlong-actingrelease,momonth,oct

octreotide,OGTToral

glucose

tolerance

test,OLopen

label,P

prospective,

pts

patients,R

randomized,Ret

retrospective,

RTradiotherapy,sc

subcutaneous,

SR

slow

release,

SSA

somatostatin

analogues,TSS

transsphenoidal

surgery,ULNupper

limitofnorm

al,wkweek,yr

year,Yyttrium

aGH\

2lg/L

bIG

F-1

towithin

norm

alrange

cGH\

5mU/L

dIG

F-1

\65nmol/L

eResponse

atlastfollow-up

fOnly

patientswhocompleted48weeksoftreatm

entin

theLancranjanetal.study[9]andhad

diagnosticGH(n

=91)orIG

F-1

(n=

67)datawereconsidered

forthisretrospectiveanalysis

Pituitary (2016) 19:235–247 239

123

Table

2SummaryoflanreotideAutogel

studiesin

acromegaly:studyparam

etersandbiochem

ical

endpoints

Publication

nTrial

design

Trial

duration

Patientpopulation

Dose

titration

GH

andIG

F-1

entry

criteria

Target

threshold

values

forGH

andIG

F-1

Biochem

ical

controlrates

Previoustreatm

ent

Priorresponse

toSSA

GH

n(%

)

IGF-1

n(%

)

GH

?IG

F-1

n(%

)

Caronet

al.

[29]

130

OL,P

12mo

TSS(n

=99);RT

(n=

57);lanSR

(n=

130);lanATG

(n=

130)

Allptshad

completeda

3-m

onth

studyoflanATG

in

whichptswereselected

based

onresponse

tolanSR

Dose

titration

accordingto

biochem

ical

response

atstudy

entry,4and8mo

–GH\

2.5

lg/L

IGF-1

norm

al

83 (6

4)

62 (4

8)

52(40)

Alexopoulou

etal.[30]

25

OL,P

24wk

TSS(n

=13);RT

(n=

5);oct

LAR

(n=

25)

Allptshad

beentreatedwithoct

LAR

atafixed

dose

forC6

mo

Dose

titration

accordingto

biochem

ical

response

at8wk

–GH\

2.5

lg/L

IGF-1

norm

al

12 (4

8)

13 (5

2)

–

Lucaset

al.

[36]

98

OL,P

12–30wk

TSS(n

=76);

radiotherapy

(n=

53);lanSR

(n=

98)

Allptshad

beentreatedwithlan

SR

forC

2moim

mediately

priorto

studyentry

Fixed

dose

GH[

2lg/L

after

OGTTandIG

F-

1[

ULN

forageand

sex

GH\

2.5

lg/L

IGF-1

norm

al

53 (5

4)

55 (5

6)

39(40)

Ronchiet

al.

[31]

23

OL,P

34–42wk

TSS(n

=16);oct

LAR

(n=

23)

Only

pts

withGH

reductionof

[50%

during6–18mo

treatm

entwithoct

LARwere

selected

Dose

titration

accordingto

biochem

ical

response

at18wk

GH

reductionof[50%

during6–18mo

treatm

entwithoct

LAR

GH\

2.5

lg/L

IGF-1

norm

al

13 (5

7)

9(39)

7(30)

Chanson

etal.[13]

63

OL,P

48wk

TSS(n

=37);RT

(n=

12);prior

medical

therapy

(n=

49)

Ptsnotselected

forprior

response

Dose

titration

accordingto

biochem

ical

response

at16and

32wk

IGF-1

C1.3xULN

GH\

2.5

lg/L

IGF-1

norm

al

53 (8

4)a

27 (4

3)a

24(38)

Attanasio

etal.[32]

27

OL,P

12mo

TSS(n

=8);denovo

(n=

19)

Ptsnotselected

forprior

response

Individualized

every

moaccordingto

biochem

ical

response

GH[

1lg/L

after

OGTTandIG

F-

1[

ULN

forageand

sex

GH\

2.5

lg/L

IGF-1

norm

al

11 (4

1)

14 (5

2)

10(37)

Andries

etal.

[28]

12

OL,R,

P,

CO

12mo

TSSalone(n

=4);

TSS?

radiotherapy

(n=

3);oct

LAR

(n=

11)

4pts

had

controlofboth

GH

andIG

F-1

atstudyentry

––

GH\

0.38lg/L

IGF-1

norm

al

5(42)

6(50)

5(42)

Colaoet

al.

[33]

26

OL,P

12mo

Denovo(n

=26)

Ptsnotselected

forprior

response

Dose

titration

accordingto

biochem

ical

response

at12wk

GH[

1lg/L

after

OGTTormean

GH[

2.5

lg/L

and

IGF-1[

ULN

forage

andsex

GH

B5mU/L

IGF-1

norm

al

15 (5

8)

15 (5

8)

14(54)

Lombardi

etal.[ 34]

63

OL,P

48–52wk

TSS(n

=12);denovo

(n=

39)b

Ptsnotselected

forprior

response

Dose

titration

accordingto

biochem

ical

response

at24wk

GH[

1lg/L

after

OGTTormean

GH[

5lg/L

andIG

F-

1[

ULN

forageand

sex

GH\

2.5

lg/L

IGF-1

norm

al

32 (5

1)

19 (3

0)

18(29)

240 Pituitary (2016) 19:235–247

123

Table

2continued

Publication

nTrial

design

Trial

duration

Patientpopulation

Dose

titration

GH

andIG

F-1

entry

criteria

Target

threshold

values

forGH

andIG

F-1

Biochem

ical

controlrates

Previoustreatm

ent

Priorresponse

to

SSA

GH

n(%

)

IGF-1

n(%

)

GH

?IG

F-1

n(%

)

Melmed

etal.[20]

107

OL,R,

P

52wk

TSS(n

=59);RT(n

=12);lan

SR

(n=

21);oct

LAR

(n=

27);oct

sc(n

=4);DA

(n=

4);denovo(n

=15)

Pts

notselected

for

priorresponse

Dose

titrationaccording

tobiochem

ical

response

at16and

32wk

GH[

3–5lg/L

GH

B2.5

lg/L

IGF-1

norm

al

55 (5

1)

62 (5

8)c

44(41)c

Salvatori

etal.[21]

26

OL,P

6mo

TSS(n

=22);oct

LAR

(n=

4);

oct

sc(n

=1);DA

(n=

6);no

priormedical

therapy(n

=15)

Pts

notselected

for

priorresponse

Dose

titrationaccording

tobiochem

ical

response

at16wk

–GH\

1.0

lg/L

post-O

GTT

IGF-1

norm

al

9(35)

10 (3

8)d

7(27)d

Schopohl

etal.[35]

37

OL,P

24–48wk

Oct

LAR

(n=

37);TSSin

an

unreported

number

ofpts

Pts

wereadequately

treatedwithoct

LAR

forC6mo

(IGF-

1B

1.3xULN)

Dose

titrationafter3

injectionsto

lanATG

every28,42or

56days

IGF-1

B1.3xULN

while

onoct

LAR

GH\

2.0

lg/L

IGF-1

norm

al

25 (6

8)e

22 (5

9)

–

Tutuncu

etal.[14]

32

OL,

Ret

18mo

TSS(n

=32)

Pts

notselected

for

priorresponse

Dose

titrationaccording

tobiochem

ical

response

at6mo

GH[

1lg

/Lafter

OGTTormean

GH[

5lg/L

and

IGF-1[

ULN

forage

andsex

GH\

2.5

lg/L

or\

1lg/L

post-O

GTT

IGF-1

norm

al

25 (7

8)

25 (7

8)

25(78)

Annam

alai

etal.[22]

30

OL,P

24wk

Denovo(n

=30)

Pts

notselected

for

priorresponse

Uptitrationin

pts

with

meanGH

C2.5

lg/L

and/orIG

F-1[

ULN

at3mo

GH[

0.4

lg/L

after

OGTTandIG

F-

1[

ULN

forageand

sex

GH\

1.0

lg/L

IGF-

1B

1.1xULN

12 (4

0)

12 (4

0)

10(33)

Shim

atsu

etal.[23]

32

OL,R,

P

24wk

TSS(n

=26),RT(n

=4),

medical

therapy(n

=13)

Pts

notselected

for

priorresponse

Fixed

dose

GH[

1.7–2.8

lg/L

GH\

2.5

lg/L

IGF-1

norm

al

17 (5

3)

14 (4

4)

13(41)

Shim

atsu

etal.[23]

32

OL,P

12mo

TSS(n

=27),RT(n

=6),

medical

therapy(n

=20)

8patients

had

completeda

previousstudyof

lanATG

Uptitrationin

pts

with

meanGH

C1.0

lg/L

and/orIG

F-1[

ULN

at4and8mo

GH[

2.5

lg/L

GH\

2.5

lg/L

IGF-1

norm

al

15 (4

7)

17 (5

3)

13(41)

ATG

Autogel,CO

crossover,DAdopam

ineagonist,GH

growth

horm

one,

IGF-1

insulin-likegrowth

factor1,lanlanreotide,

LARlong-actingrelease,

momonth,oct

octreotide,

OGTToral

glucose

tolerance

test,OLopen

label,P

prospective,

pts

patients,R

randomized,Ret

retrospective,

RTradiotherapy,sc

subcutaneous,

SR

slow

release,

SSA

somatostatin

analogues,TSS

transsphenoidal

surgery,ULNupper

limitofnorm

al,wkweek,yr

year

a35%

ofpatientshad

GH

B2.5

lg/L

atbaseline

bAnunreported

number

ofpatients

had

received

B3months’

presurgical

treatm

entwithSSA

cIG

F-1

levelswerenorm

alin

10%

ofpatients

atbaseline

dIG

F-1

levelswerenorm

alin

15%

ofpatients

atbaseline

eAtbaseline,

28patients(76%)had

GH

levels\

2.0

lg/L

Pituitary (2016) 19:235–247 241

123

recipients achieved both GH and IGF-1 control after 1 year

of treatment. When patients were stratified by prior treat-

ment, the response rates in de novo patients were 17 and

26 % for octreotide LAR and pasireotide LAR, respec-

tively, compared with 22 and 39 % in patients who had

received prior surgery. Interestingly, in a 52-week study of

lanreotide Autogel, 55 % of patients who had received

prior treatment with a somatostatin analogue achieved

biochemical control, compared with 20 % of somatostatin-

analogue-naıve patients [20].

Although there are other factors that may have con-

tributed to the relatively low response rates in these more

recent studies, these results suggest that response rates in

studies of patients with de novo acromegaly are generally

lower than response rates in prospective studies of patients

who have previously received transsphenoidal surgery and/

or radiotherapy and/or somatostatin analogues. This is

consistent with a number of studies that showed that by

reducing tumor mass and, therefore, decreasing basal GH

secretion, subsequent control of GH and IGF-1 levels with

somatostatin analogues may be improved [38–42].

Heterogeneity in the definition of biochemical

control

The two parameters of biochemical control, suppression of

excess GH secretion to predefined threshold levels and

normalization of serum IGF-1 levels, are used as the pri-

mary markers of efficacy in most clinical trials of

somatostatin analogues in patients with acromegaly. From

the studies fulfilling the search criteria (Tables 1, 2), target

threshold levels are generally similar across all the studies

(the majority use GH B 2.5 lg/L and normal IGF-1 for age

and sex). However, studies published before 2006 gener-

ally reported response rates for GH and IGF-1 separately

[5–9, 24, 25, 30], rather than the percentage of patients who

achieved control of both GH and IGF-1 levels (Fig. 1).

Evaluation of GH or IGF-1 separately, rather than as a

composite endpoint, was employed in ‘early’ clinical

studies (1996–2006) [5–9, 24, 25, 30] and resulted in

response rates that were relatively high compared with

those in studies reported after 2006 (Fig. 1). The literature

around this ‘early’ period began to report that patients with

Fig. 1 Biochemical response rates to octreotide LAR and lanreotide

Autogel reported in the medical literature by publication year and

stratified according to whether GH and IGF-1 were reported as

separate efficacy endpoints or as a composite efficacy endpoint.

M = prior surgery but medically naive; N = treatment naive;

T = previously treated with surgery and/or radiotherapy and/or

medical therapy

242 Pituitary (2016) 19:235–247

123

GH levels B2.5 lg/L did not necessarily achieve normal-

ization of IGF-1 levels [43]. Indeed, approximately 25 %

[6, 43] of patients were suggested to have discrepant GH

and IGF-1 control (control of GH without IGF-1 control, or

vice versa). As a consequence, the measurement of a

composite efficacy endpoint of control of both GH and

IGF-1 levels was advocated [44] and subsequently rec-

ommended by clinical practice guidelines for assessing

biochemical response [1]. These findings likely prompted a

shift away from only reporting GH and IGF-1 separately

towards the more stringent composite measure and, as

might be expected, the majority of the more recent studies

(2007–2014) [6, 11, 12, 15–19] are generally associated

with relatively low response rates (Fig. 1). Thus, hetero-

geneity in the definition of biochemical control may be a

contributing factor giving rise to differences in reported

response rates.

Study design and nuances of the study protocol

Prospective versus retrospective

Although both prospective and retrospective studies pro-

vide valuable data, retrospective studies are more likely to

contain elements of bias and confounding. One of the

main elements of bias associated with retrospective

studies is the inclusion of only those patients who com-

pleted a certain duration of treatment and were not lost to

follow-up or did not discontinue treatment because of

adverse events or other reasons. For example, the retro-

spective study by Cozzi et al. [6], which reported a GH

response rate of 72 % and an IGF-1 response rate of

75 %, excluded an unreported number of patients who

received octreotide LAR for less than 18 months. Had all

patients who started on octreotide LAR been included in

the analysis, the reported response rates may have been

lower, as patients not reaching 18 months of therapy may

have discontinued treatment because of non-response.

Similarly, the retrospective comparison by Tutuncu et al.

[14] of octreotide LAR and lanreotide Autogel in patients

who had failed surgery reported that 64 % of octreotide

LAR patients and 78 % of lanreotide Autogel patients had

biochemical control after 18 months of treatment. How-

ever, the analysis retrospectively excluded all patients

who had required a second operation or who had received

additional medical treatment within 18 months of the

initial surgery (i.e., probable non-responders to octreotide

or lanreotide), thus artificially increasing response rates.

As can be seen in Fig. 1, retrospective studies generally

result in higher response rates, and the main reason is

usually the retrospective exclusion of non-responders

from the analysis.

Per protocol or intention to treat

However, many prospective studies also exclude patients

who did not complete the study. For example, the

prospective, 1-year follow-up study of lanreotide Autogel

by Caron et al. [29] enrolled 130 patients previously treated

with surgery and/or lanreotide Autogel, yet nine patients

were excluded from the final analysis of biochemical

control. Although the reasons for exclusion from the

analysis may appear valid from a clinical practice per-

spective, for example, patients dropped out before the first

efficacy analysis or withdrew consent to remain on treat-

ment, these patients should be included as non-responders

in an intention-to-treat (ITT) analysis. Therefore, although

the study reported that 43 % (52/121) of the ITT popula-

tion achieved biochemical control [29], the actual response

rate was 40 % (52/130) (Table 2).

An efficacy analysis conducted on either the per-proto-

col (PP) or ITT population can produce significantly dif-

ferent outcomes. In an ITT analysis, all patients who were

enrolled are considered part of the study, whether they

receive treatment, complete the study or not. A PP analysis,

however, is based on the population of patients who

completed the clinical trial without any major protocol

violations. For example, the study by Mercado et al. [18]

reported results based on the PP population. This

prospective, multicenter study evaluated octreotide LAR as

first-line therapy in 98 previously untreated patients for

1 year. At month 12, 30 patients were excluded from the

efficacy analysis because of either major protocol viola-

tions or early discontinuation; therefore, 68 patients formed

the PP population. Seventeen patients achieved biochemi-

cal control (GH B 2.5 lg/L and normalization of IGF-1

levels), which corresponds to a response rate of 25 % (17/

68) based on the PP analysis, but 17.3 % (17/98) based on

analysis of the ITT population (Table 1). Thus, analysis of

the PP population usually leads to the reporting of higher

response rates than an analysis of all patients who were

intended to be treated.

Definition of responders and non-responders

Open-ended studies that report patients’ response at last

follow-up generally result in a higher overall response rate

than studies with a fixed time point to evaluate response.

Although the definition of response may be the same with

respect to the biochemical parameters (e.g., GH B 2.5 lg/L and normal IGF-1), the time point at which biochemical

control is measured may differ. In the study by Cozzi et al.

[12], 56.7 % of previously untreated patients were reported

to have achieved biochemical control (GH B 2.5 lg/L and

normal IGF-1). Patients in this study were followed up for

6–108 months, and their response at last follow-up was

Pituitary (2016) 19:235–247 243

123

considered. As such, the 56.7 % of patients who were

considered responders had achieved a response at some

point between months 6 and 108 and so should not be

compared with studies of a similar patient population that

reported response rates at a specific time point, for exam-

ple, at month 12 of treatment.

Furthermore, the pre-specified definition of biochemical

control should be adhered to during analysis of the results.

Like most studies, the randomized, double-blind study of

pasireotide LAR versus octreotide LAR by Colao et al. [19]

defined biochemical control as GH\ 2.5 lg/L and normal

IGF-1 at month 12. In this study, a patient with IGF-1

below the lower limit of normal was not considered a

responder for the primary analysis because IGF-1 was

abnormal. The consequence of this protocol definition is

best exemplified by a post hoc analysis which included

these patients with IGF-1 below the lower limit of normal

as responders: response rates for octreotide LAR and

pasireotide LAR increased from 19.2 to 20.9 % and from

31.3 to 35.8 %, respectively [19]. These examples

emphasize the importance of appreciating the definitions of

responders in study protocols and how they are treated in

the primary analysis.

Assay variability

A wide range of immunoassays are used for the assessment

of GH and IGF-1 levels. However, considerable hetero-

geneity in assay characteristics exists, which may lead to

variability in results. This assay variability can be largely

classified into two categories: cross-sectional variation,

where different assays give differing results [45, 46]; and

longitudinal variation, in which assays are unstable over

time [47]. The lack of standardization between assays is of

such concern that a 2011 consensus statement on the

standardization and evaluation of GH and IGF-1 assays

was developed as part of an international effort to harmo-

nize GH and IGF-1 assays [48]. For the purposes of the

current review, an analysis of the assays used in each study

has not been undertaken. However, it is likely that some of

the variability in GH and IGF-1 response rates seen in

studies in this review is due to assay variability.

Response rates in a clinical trial setting: summary

Using representative examples of different clinical trial

protocols evaluating octreotide LAR and lanreotide

Autogel as a treatment for acromegaly, it is evident that

multiple factors are capable of impacting on reported

response rates. Prospective studies reporting an ITT

analysis that evaluated medically naıve patients, used the

composite endpoint of both GH and IGF-1 control, and

used a fixed time point to evaluate response were asso-

ciated with lower response rates. The use of less strin-

gent non-composite biochemical control endpoints,

heterogeneous patient populations, study protocols that

exclude treatment non-responders from the efficacy

analysis, and prior responsiveness to medical therapy are

just a few of the factors identified that likely contribute

to higher success rates. This review does not attempt to

place emphasis on any one particular factor over another,

but it serves instead to raise awareness of the dangers of

interpreting biochemical control response rates without

first carefully considering how the study design, patient

population and statistical analysis might impact on the

data. Multivariate statistical analyses exploring the dif-

ferences in response rates between studies would help to

quantify the impact these factors may have on reported

outcomes, and such an analysis is encouraged. With this

in mind, it is perhaps unsurprising that response rates to

somatostatin analogues, or to agents of any class of drug,

in published clinical trials vary considerably.

Response rates in clinical practice

In clinical practice, biochemical response rates to

somatostatin analogues are likely to fall somewhere

between the rates observed in the early clinical trials and

the rates observed in more recent trials. Many patients

seen in the clinic are post-surgical or have had suc-

cessful prior treatment with a somatostatin analogue,

rather than being treatment naıve. Prior to treatment with

somatostatin analogues, patients may also be ‘pre-se-

lected’ for potential responsiveness with an acute

octreotide suppression test [49]. The clinical setting

allows for dose adjustments at the discretion of the

physician and long-term treatment, both of which pro-

vide opportunities for higher response rates, similar to

long-term, open-label studies. The choice of parameters

used to gauge clinical response also plays a significant

role in perceived treatment success; both GH and IGF-1

levels together as a composite measure should be used to

assess biochemical response [2, 50].

Finally, similar to the differences in clinical trials of

reporting data from patients who discontinue treatment

(e.g., ITT vs. PP analysis), clinicians (including those from

specialist pituitary centers) sometimes might remember

only those patients who have responded to treatment, rather

than those who have transitioned to another treatment or

care provider. As a result, clinicians should be cautious of

comparing response rates in real-world clinical scenarios

with response rates obtained from a controlled trial setting.

As the mechanisms involved in the resistance to

somatostatin analogues become better understood, it should

244 Pituitary (2016) 19:235–247

123

be possible to predict which patients will respond to dif-

ferent medical therapies based on biomarkers. Therefore, a

more successful outcome may be observed if individual-

ized treatment is based on information such as the

somatostatin receptor subtype profile, aryl hydrocarbon

receptor-interacting protein (AIP) expression, and T2

intensity on magnetic resonance imaging, among others

[51, 52]. This would result in higher response rates,

because those patients who would not have responded to

treatment with a particular agent would not be unneces-

sarily treated.

Concluding remarks

As acromegaly is a rare disorder, even experienced

endocrinologists may seldom treat a patient with acrome-

galy and therefore rely on the medical literature to inform

treatment decision making. However, the wide range of

reported response rates with octreotide LAR and lanreotide

Autogel may be confusing and could lead to misinterpre-

tation by both the patient and the physician in certain sit-

uations. Understanding the factors that potentially drive the

discordance in response rates, as reported in this review,

should allow clinicians to better gauge treatment expecta-

tions in specific patients.

Acknowledgments We thank Keri Wellington PhD, Mudskipper

Business Ltd, for medical editorial assistance with this manuscript.

Funding Financial support for medical editorial assistance was

provided by Novartis Pharmaceuticals Corporation.

Compliance with ethical standards

Conflict of interest RSA and LK have nothing to disclose. AC has

been principal investigator of Novartis, Ipsen and Pfizer research

studies, has received research grants from Novartis, Ipsen, Pfizer,

Ferring, Lilly, Novo Nordisk, HRA Pharma and Italfarmaco, has been

an occasional consultant for Novartis, Ipsen, Pfizer and Italfarmaco,

and has received lecture fees and honoraria from Novartis and Ipsen.

RP has been principal investigator of Novartis research studies, has

received research grants from Novartis, Pfizer, Viropharma and IBSA,

has been an occasional consultant for Novartis, Ipsen, Pfizer, Vir-

opharma, Ferring and Italfarmaco, and has received lecture fees and

honoraria from Novartis. MRG has received research grants from

Novartis and Pfizer, has been principal investigator for Novartis and

Ipsen clinical trials, has served on advisory boards for Novartis, and

has received lecture fees from Novartis, Ipsen and Pfizer.

Open Access This article is distributed under the terms of the

Creative Commons Attribution 4.0 International License (http://crea

tivecommons.org/licenses/by/4.0/), which permits unrestricted use,

distribution, and reproduction in any medium, provided you give

appropriate credit to the original author(s) and the source, provide a

link to the Creative Commons license, and indicate if changes were

made.

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